Insights into the structure of NLR family member X1: Paving the way for innovative drug discovery

Abstract

Nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) is a negative regulator of the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway, with a significant role in the context of inflammation. Altered expression of NLRX1 is prevalent in inflammatory diseases leading to interest in NLRX1 as a drug target. There is a lack of structural information available for NLRX1 as only the leucine-rich repeat domain of NLRX1 has been crystallised. This lack of structural data limits progress in understanding function and potential druggability of NLRX1. We have modelled full-length NLRX1 by combining experimental, homology modelled and AlphaFold2 structures. The full-length model of NLRX1 was used to explore protein dynamics, mutational tolerance and potential functions. We identified a new RNA binding site in the previously uncharacterized N-terminus, which served as a basis to model protein-RNA complexes. The structure of the adenosine triphosphate (ATP) binding domain revealed a potential catalytic functionality for the protein as a member of the ATPase Associated with Diverse Cellular Activity family of proteins. Finally, we investigated the interactions of NLRX1 with small molecule activators in development, revealing a binding site that has not previously been discussed in literature. The model generated here will help to catalyse efforts towards creating new drug molecules to target NLRX1 and may be used to inform further studies on functionality of NLRX1.

Keywords

• Inflammation
• NLRX1
• Inflammasome
• ATPase